Treprostinil derivative, and preparation method therefor and use thereof

Abstract

The present invention relates to the field of chemistry and medicine. Provided is a treprostinil derivative represented by formula I, or an isomer or a pharmaceutically acceptable salt thereof, wherein each group is as defined in the description. The compound of formula I, or the isomer or the pharmaceutically acceptable salt thereof can remain in the lung for a long time and slowly release treprostinil at an effective concentration after pulmonary administration, and can therefore be used for treating pulmonary hypertension and pulmonary fibrosis. The pulmonary administration of the compound of formula I, or the isomer or the pharmaceutically acceptable salt thereof provided in the present invention can greatly reduce the administration dosage, provide a lower administration frequency and a broader therapeutic window, and reduce systemic side effects and local lung irritation. Therefore, the drug safety and drug tolerance of a patient are greatly improved, and a new treatment choice is provided for a patient with pulmonary hypertension and pulmonary fibrosis.

Description

A treprostinil derivative, its preparation method and application Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a treprostinil derivative as shown in Formula I, a preparation method and application thereof. Background Art

[0002] Pulmonary hypertension (PH) refers to a clinical pathophysiological syndrome characterized by a mean pulmonary artery pressure ≥25 mmHg measured by right catheter at rest at sea level. It is characterized by pulmonary vascular lesions and remodeling, arterial stenosis and impaired vasodilation, increased pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR), which limit the right ventricle's ability to pump blood to the lungs through the pulmonary artery, leading to shortness of breath and ultimately right heart failure and death. PH is caused by a variety of heterogeneous diseases (etiologies) and different pathogenesis. Clinically, PH is divided into five major categories: (1) arterial PH (PAH); (2) PH caused by left heart disease; (3) PH caused by lung disease and / or hypoxia; (4) PH caused by chronic thromboembolic PH (CTEPH) and / or other pulmonary artery obstructive lesions; and (5) PH caused by unknown and / or multiple factors.

[0003] According to statistics, the prevalence of pulmonary hypertension in the general population is approximately 1%, but the incidence rises to 10% in people over 65 years of age. Among all types of PH, PH caused by left heart disease, lung disease, and / or hypoxia is the most common type in clinical practice. Among PH caused by lung disease and / or hypoxia, COPD, interstitial lung disease, and pulmonary fibrosis are the most common causes of this type of PH. The cause of idiopathic PAH (IPAH) is currently unknown. Although PAH has a low incidence, it is known as the "cancer of the cardiovascular system." Epidemiological data show that the 5-year survival rate of patients with idiopathic and hereditary PAH after conventional treatment is only 20.8%. Moreover, due to the lack of professional disease management capabilities and effective doctor-patient communication methods, most patients with pulmonary hypertension do not maintain ideal disease control even after discharge.

[0004] Currently, PAH treatment still mainly targets three signaling pathways: prostacyclin (PGI2), endothelin-1 (ET-1), and nitric oxide (NO). Among them, the PGI2 signaling pathway is the most important and is the only drug among the three major targeted drugs that can reduce the mortality rate of PAH patients. PGI2 is an effective vasodilator that binds to prostaglandin receptors (IP receptors, EP receptors) to activate adenylate cyclase, thereby increasing the concentration of intracellular cAMP and playing a role in dilating blood vessels. In addition, PGI2 also has antiplatelet formation, antiproliferative and anti-inflammatory effects. In PAH patients, the amount of PGI2 synthesized in the body is reduced and the expression of IP receptors is reduced. PGI2 analogs work by simulating the binding of PGI2 to IP receptors.

[0005] Currently marketed prostacyclins primarily include epoprostanol, iloprost, beraprost, and treprostinil. Most are expensive, have short half-lives, poor chemical stability, and significant side effects. They often require continuous intravenous or subcutaneous infusion, and are associated with severe injection site pain and infection. If the intravenous infusion is abruptly interrupted, patients may be at risk for fatal rebound pulmonary hypertension. Although treprostinil is available as an inhaled formulation (trade name Tyvaso) for the treatment of PAH and has demonstrated efficacy in clinical studies in patients with idiopathic interstitial pneumonia (IIP), including idiopathic fibrosis (IPF) and pulmonary fibrosis with emphysema (CPFE), its short half-life (approximately 30 minutes) requires frequent dosing to maintain pulmonary vasodilation. In addition, inhaled treprostinil is associated with local and systemic adverse events, including cough, headache, and throat irritation, which affect tolerability and efficacy and complicate its clinical application.

[0006] To overcome these shortcomings, researchers have evaluated a number of alternative therapeutic strategies, including liposome encapsulation, novel drug delivery devices, particle engineering using modern technologies, and prodrug modification of treprostinil. Insmed has developed treprostinil palmitate (C16-TR), an ester prodrug of treprostinil that hydrolyzes slowly and releases treprostinil over an extended period. The structural formulas of treprostinil and C16-TR are shown below.

[0007] C16-TR is a long-acting prodrug designed to improve patient compliance and reduce the toxic side effects of systemic administration through inhalation. Clinical studies have shown that C16-TR has a good therapeutic effect. At a lower dose (54 μg / kg), subjects did not experience coughing or sore throat side effects, but as the dose increased (170 μg / kg and 340 μg / kg), subjects developed coughing and sore throat. Due to the physical and chemical properties of the C16-TR compound itself, it cannot be used directly as a nebulized inhalation solution. Initial formulation work focused on developing a solid lipid nanoparticle (LNP) and using PEG-modified lipids to increase the stability of the drug and particles. The LNP particles were then prepared into a suspension for delivery to the lungs. However, this formulation technology is complex and expensive, with high industrial costs, and patients may need to bear high drug treatment costs. There are currently no commercial inhalation products using LNP technology, and the long-term safety of its complex excipient components in the lungs has not yet been certified by regulatory agencies. During aerosol development, C16-TR had limited solubility in ethanol-supplemented HFA propellants, necessitating the addition of surfactants such as DSPE-PEG for solubilization. Long-term exposure to high doses of PEGylated lipids could potentially cause pulmonary toxicity. Because PEGylated lipids are immunogenic, long-term use could also lead to adverse effects such as immune responses. Furthermore, C16-TR has been reported to react with ethanol in its dissolved state, with the C16 ester being replaced by the ethyl ester. Consequently, C16-TR presents significant challenges in formulation development.

[0008] In summary, exploring more suitable compounds or dosage forms, further improving the in vivo metabolic characteristics of treprostinil to reduce the dosage and frequency of use, and reduce toxic side effects; improving the physical and chemical properties of the compound, reducing the cost of the formulation industry, providing patients with safer, more convenient, and more economical medication plans, improving the quality of life of patients, and prolonging their survival, has very positive and far-reaching clinical value.

[0009] Summary of the Invention

[0010] In view of the problems existing in the prior art, the present invention provides a treprostinil derivative and its medical use.

[0011] In one aspect, the present invention provides a compound represented by Formula I, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0012] in,

[0013] Each X is independently selected from O or S;

[0014] A is a cyclic group selected from phenyl, 5- to 10-membered heteroaryl, wherein the heteroatom in the 5- to 10-membered heteroaryl is selected from one or more of N, O, and S;

[0015] R 1 、R 2 Each is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, hydroxy, amino, cyano, nitro, or -ONO2, or R 1 、R 2 Together with the carbon atoms to which they are attached, they form a cyclic group, wherein the C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy is optionally substituted by one or more substituents selected from the following groups: cycloalkyl, aryl, heteroaryl, -NR 3 R 4 , halogen atoms, hydroxyl groups, cyano groups, mercapto groups, nitro groups or -ONO2;

[0016] R 3 、R 4 are each independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, or R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 5-8 membered heterocyclic ring;

[0017] Each Y is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, carboxyl, cyano, thiol, C1-C6 alkoxy, C1-C6 alkylamino, or 3-8 membered cycloalkyl;

[0018] m is an integer from 4 to 16;

[0019] n is an integer from 0 to 8;

[0020] j is an integer from 0 to 2;

[0021] k is an integer from 0 to 3.

[0022] In certain embodiments, A is phenyl; or A is a 5- to 8-membered heteroaryl (eg, pyridyl), wherein the heteroatom in the 5- to 8-membered heteroaryl is N.

[0023] In certain embodiments, each X is independently O.

[0024] According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Each independently selected from H or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, an amino group, a nitro group, -ONO2, and a mercapto group.

[0025] According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof according to the present invention, wherein each Y is independently selected from C1-C6 alkyl, halogen, cyano, or C1-C6 alkoxy, preferably halogen, C1-C6 alkyl, and more preferably chlorine.

[0026] According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof of the present invention, wherein Y is an ortho- or para-substituent.

[0027] According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof, m is an integer from 6 to 10.

[0028] According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof of the present invention, wherein n is an integer from 2 to 8, preferably an integer from 4 to 6.

[0029] According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof of the present invention, wherein j is an integer from 0 to 1.

[0030] According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof of the present invention, wherein k is an integer from 0 to 2.

[0031] According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof, the compound is selected from:

[0032] According to the present invention, the compound of formula I, its isomer or pharmaceutically acceptable salt thereof can be continuously and slowly converted into treprostinil, and has good solubility and stability in alcohol solvents, especially when X is O, j is 0, and A is phenyl.

[0033] The second aspect of the present invention provides an isotope-substituted compound of the above formula I, its isomers or pharmaceutically acceptable salts thereof, preferably a deuterium-substituted compound.

[0034] The compound of Formula I, its isomers, pharmaceutically acceptable salts, or isotopic substitutions provided by the present invention, due to its unique ester side chain structure, has unique diffusion microdynamic characteristics in the lungs after pulmonary administration. The lipophilic side chain structure is highly distributed in the phospholipid layer on the cell membrane surface, allowing the compound of Formula I to slowly convert and release treprostinil in the local microenvironment around the receptor. The released treprostinil can diffuse more effectively to the prostaglandin receptor binding site on the cell surface, thereby exerting an effective and long-lasting drug effect.

[0035] The third aspect of the present invention provides a pharmaceutical composition comprising at least one compound of the aforementioned formula I, its isomers or pharmaceutically acceptable salts, or isotope substitutions thereof, and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients include: carriers, diluents, excipients, etc.

[0036] According to the pharmaceutical composition of the present invention, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg, preferably 0.001 mg-500 mg, preferably 0.001 mg-100 mg, and more preferably 0.001 mg-10 mg.

[0037] The pharmaceutical composition according to the present invention, wherein, based on the total weight of the composition, the pharmaceutical composition contains 0.01%-99.99% of the aforementioned compound. The pharmaceutical composition according to the present invention, wherein, the pharmaceutical composition contains 0.01%-90% of the aforementioned compound. The pharmaceutical composition according to the present invention, wherein, the pharmaceutical composition contains 0.01%-80% of the aforementioned compound. The pharmaceutical composition according to the present invention, wherein, the pharmaceutical composition contains 0.01%-70% of the aforementioned compound. The pharmaceutical composition according to the present invention, wherein, the pharmaceutical composition contains 0.01%-60% of the aforementioned compound. The pharmaceutical composition according to the present invention, wherein, the pharmaceutical composition contains 0.01%-50% of the aforementioned compound. The remaining weight of the composition is contributed by pharmaceutically acceptable carriers, diluents or excipients.

[0038] According to the pharmaceutical composition of the present invention, the pharmaceutical composition may further comprise other active agents in addition to the compound of the present invention.

[0039] The fourth aspect of the present invention provides the use of the compound of formula I, its isomers or pharmaceutically acceptable salts, or isotope substitutes, or pharmaceutical compositions of the present invention in the preparation of a medicament for treating pulmonary hypertension (PH).

[0040] The fifth aspect of the present invention provides the use of the compound of formula I, its isomers or pharmaceutically acceptable salts or isotope substitutes, or pharmaceutical compositions thereof in the preparation of drugs for treating pulmonary fibrosis.

[0041] According to the use of the present invention, the use comprises administering to the patient an effective amount of the aforementioned compound of formula I, its isomer or pharmaceutically acceptable salt, isotope substitution, or pharmaceutical composition.

[0042] According to the use of the present invention, the administration method is subcutaneous, oral, nasal, intravenous or pulmonary administration, preferably, the administration method is pulmonary administration.

[0043] According to the use of the present invention, the pulmonary administration includes administration via a metered dose inhaler, a dry powder inhaler, an atomizing sprayer, or a soft mist inhaler.

[0044] According to the use of the present invention, the pulmonary administration includes administration via a metered dose inhaler.

[0045] According to the use of the present invention, the pulmonary administration includes administration via a dry powder inhaler.

[0046] According to the use of the present invention, the pulmonary administration includes administration via an atomizing nebulizer.

[0047] According to the use of the present invention, the pulmonary administration includes administration via a soft mist inhaler.

[0048] According to the use of the present invention, the patient suffering from pulmonary hypertension is a World Health Organization (WHO) Group I PH patient, or a WHO Group II PH patient, or a WHO Group III PH patient, or a WHO Group IV PH patient, or a WHO Group V PH patient.

[0049] According to the use of the present invention, the pulmonary hypertension is selected from pulmonary arterial hypertension (PAH), pulmonary hypertension caused by left heart disease, pulmonary hypertension caused by lung disease and / or hypoxia, chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary hypertension caused by pulmonary artery obstructive lesions, and pulmonary hypertension associated with systemic or metabolic diseases.

[0050] According to the use of the present invention, the pulmonary arterial hypertension (PAH) is selected from idiopathic pulmonary arterial hypertension, hereditary pulmonary arterial hypertension, congenital heart disease-related pulmonary arterial hypertension, portal hypertension-related pulmonary arterial hypertension, and drug- or poison-related pulmonary arterial hypertension.

[0051] According to the use of the present invention, the pulmonary arterial hypertension (PAH) is idiopathic pulmonary arterial hypertension.

[0052] According to the use of the present invention, the pulmonary arterial hypertension (PAH) is hereditary pulmonary arterial hypertension.

[0053] According to the use of the present invention, the pulmonary arterial hypertension (PAH) is portal hypertension-related pulmonary arterial hypertension.

[0054] According to the use of the present invention, the pulmonary hypertension (PH) is pulmonary hypertension caused by left heart disease.

[0055] According to the use of the present invention, the pulmonary hypertension (PH) is pulmonary hypertension caused by lung disease and / or hypoxia. The pulmonary hypertension caused by lung disease and / or hypoxia is pulmonary hypertension associated with interstitial lung disease (ILD-PH), pulmonary hypertension caused by chronic obstructive pulmonary disease, and pulmonary hypertension caused by pulmonary fibrosis combined with emphysema.

[0056] According to the use of the present invention, the pulmonary hypertension (PH) is chronic thromboembolic pulmonary hypertension.

[0057] According to the use of the present invention, the pulmonary hypertension (PH) is pulmonary hypertension associated with systemic or metabolic diseases.

[0058] According to the use of the present invention, the pulmonary hypertension associated with systemic or metabolic diseases is sarcoidosis-related pulmonary hypertension.

[0059] According to the use of the present invention, the pulmonary fibrosis disease is selected from pulmonary interstitial fibrosis caused by idiopathic interstitial pneumonias (IIPs) and pulmonary interstitial fibrosis caused by connective tissue diseases.

[0060] According to the use of the present invention, the pulmonary interstitial fibrosis caused by idiopathic interstitial pneumonias (IIPs) is idiopathic fibrosis (IPF).

[0061] According to the use of the present invention, the administration is to administer an effective amount of the compound of formula I, its isomer or pharmaceutically acceptable salt, its isotope substitution, or pharmaceutical composition to the patient once a day.

[0062] According to the use of the present invention, an effective amount of the compound of formula I, its isomer or pharmaceutically acceptable salt, its isotope substitute, or pharmaceutical composition is administered to the patient once every two days, or at a longer dosing interval.

[0063] According to the use of the present invention, the administration is to administer an effective amount of the compound of formula I, its isomer or pharmaceutically acceptable salt, its isotope substitution, or pharmaceutical composition to the patient twice a day.

[0064] The sixth aspect of the present invention provides a method for treating pulmonary hypertension (PH), comprising administering to a patient an effective amount of the aforementioned compound of formula I, its isomer or pharmaceutically acceptable salt, or isotope substitute, or pharmaceutical composition.

[0065] The seventh aspect of the present invention provides a method for treating pulmonary fibrosis, comprising administering to a patient an effective amount of the aforementioned compound of formula I, its isomer or pharmaceutically acceptable salt, or isotope substitute, or pharmaceutical composition.

[0066] According to the treatment method of the present invention, the administration method is subcutaneous, oral, nasal, intravenous or pulmonary administration, preferably, the administration method is pulmonary administration.

[0067] According to the treatment method of the present invention, pulmonary administration includes administration via a metered dose inhaler, a dry powder inhaler, a nebulizer, or a soft mist inhaler.

[0068] According to the method of treatment of the present invention, pulmonary administration comprises administration via a metered dose inhaler.

[0069] According to the method of treatment of the present invention, pulmonary administration comprises administration via a dry powder inhaler.

[0070] According to the treatment method of the present invention, the pulmonary administration includes administration via an atomizing nebulizer.

[0071] According to the method of treatment of the present invention, the pulmonary administration comprises administration via a soft mist inhaler.

[0072] According to the method for treating pulmonary hypertension of the present invention, the patient is a World Health Organization (WHO) Group I PH patient, or a WHO Group II PH patient, or a WHO Group III PH patient, or a WHO Group IV PH patient, or a WHO Group V PH patient.

[0073] According to the method for treating pulmonary hypertension of the present invention, the pulmonary hypertension is selected from pulmonary arterial hypertension (PAH), pulmonary hypertension caused by left heart disease, pulmonary hypertension caused by lung disease and / or hypoxia, chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary hypertension caused by pulmonary artery obstructive lesions, and pulmonary hypertension associated with systemic or metabolic diseases.

[0074] According to the method for treating pulmonary hypertension of the present invention, the pulmonary arterial hypertension (PAH) is selected from idiopathic pulmonary arterial hypertension, hereditary pulmonary arterial hypertension, congenital heart disease-related pulmonary arterial hypertension, portal hypertension-related pulmonary arterial hypertension, and drug- or poison-related pulmonary arterial hypertension.

[0075] According to the method for treating pulmonary hypertension of the present invention, the pulmonary arterial hypertension (PAH) is idiopathic pulmonary arterial hypertension.

[0076] According to the method for treating pulmonary hypertension of the present invention, the pulmonary arterial hypertension (PAH) is hereditary pulmonary arterial hypertension.

[0077] According to the method for treating pulmonary hypertension of the present invention, the pulmonary arterial hypertension (PAH) is portal hypertension-related pulmonary arterial hypertension.

[0078] According to the method for treating pulmonary hypertension of the present invention, the pulmonary hypertension (PH) is pulmonary hypertension caused by left heart disease.

[0079] According to the method for treating pulmonary hypertension of the present invention, the pulmonary hypertension (PH) is pulmonary hypertension caused by lung disease and / or hypoxia. The pulmonary hypertension caused by lung disease and / or hypoxia is pulmonary hypertension associated with interstitial lung disease (ILD-PH), pulmonary hypertension caused by chronic obstructive pulmonary disease, and pulmonary hypertension caused by pulmonary fibrosis combined with emphysema.

[0080] According to the method for treating pulmonary hypertension of the present invention, the pulmonary hypertension (PH) is chronic thromboembolic pulmonary hypertension.

[0081] According to the method for treating pulmonary hypertension of the present invention, the pulmonary hypertension (PH) is pulmonary hypertension associated with systemic or metabolic diseases.

[0082] According to the method for treating pulmonary hypertension of the present invention, the pulmonary hypertension associated with systemic or metabolic diseases is sarcoidosis-related pulmonary hypertension.

[0083] According to the method for treating pulmonary fibrosis of the present invention, the pulmonary fibrosis is pulmonary interstitial fibrosis caused by idiopathic interstitial pneumonias (IIPs) or pulmonary interstitial fibrosis caused by connective tissue diseases.

[0084] According to the method for treating pulmonary fibrosis of the present invention, the pulmonary interstitial fibrosis caused by idiopathic interstitial pneumonias (IIPs) is idiopathic fibrosis (IPF).

[0085] According to the treatment method of the present invention, the administration is to administer the effective amount of the compound of formula I, its isomer or pharmaceutically acceptable salt, its isotope substitution, or pharmaceutical composition to the patient once a day.

[0086] According to the treatment method of the present invention, an effective amount of the compound of formula I, its isomer or pharmaceutically acceptable salt, its isotope substitution, or pharmaceutical composition is administered to the patient once every two days or at a longer dosing interval.

[0087] According to the treatment method of the present invention, the administration is to administer an effective amount of the compound of formula I, its isomer or pharmaceutically acceptable salt, its isotope substitution, or pharmaceutical composition to the patient twice a day.

[0088] According to the method for treating pulmonary hypertension of the present invention, compared with the corresponding lung and plasma drug exposure after intravenous administration of treprostinil, the compound of formula I, its isomer or pharmaceutically acceptable salt, its isotope substitution, or pharmaceutical composition and treatment method of the present invention can provide patients with greater treprostinil lung C max and AUC, i.e., providing a greater lung-to-plasma drug exposure ratio.

[0089] According to the method for treating pulmonary hypertension of the present invention, the lung elimination half-life (t 1 / 2 ), after treating a patient with the compound of formula I, its isomers or pharmaceutically acceptable salts, its isotopic substitutions, or pharmaceutical compositions and methods of treatment of the present invention, a longer lung elimination half-life of treprostinil can be produced in the lungs, thereby greatly enhancing the retention time of treprostinil in the lungs.

[0090] According to the method for treating pulmonary hypertension of the present invention, the average lung drug-time area under the curve (AUC 0-t ), the compound of formula I, its isomer or pharmaceutically acceptable salt, its isotope substitution, or pharmaceutical composition and treatment method of the present invention can provide a greater average lung AUC after treatment of the patient. 0-t .

[0091] According to the method for treating pulmonary hypertension of the present invention, patients who are administered the compound of Formula I, its isomers or pharmaceutically acceptable salts, or isotopic substitutions, or compositions of the present invention for the treatment of PH, PAH, PPH, ILD-PH, CTEPH, or IPF experience a reduced number of side effects or a reduced severity of side effects compared to the number and / or severity of side effects experienced by the patient when treprostinil is administered. In certain embodiments, the side effect is a cough reaction of the patient, and the frequency and / or severity of the cough reaction experienced by the patient when treprostinil is administered is reduced.

[0092] The eighth aspect of the present invention provides a method for preparing the compound of formula I, comprising the following steps:

[0093] The compound of formula II is reacted with the compound of formula III to produce the compound of formula I

[0094] Wherein W is -OH, -Cl or -OC(O)R c , where R c is a C1-C5 alkyl group;

[0095] Wherein, Z is selected from -OH, -Cl, -Br, -I; Y, A, R 1 、R 2 , X, n, j, m and k are as defined above.

[0096] When W is -OH and Z is selected from -Cl, -Br, or -I, the compound of formula (II) reacts with the compound of formula (III) in the presence of a base in an inert solvent to produce the compound of formula I. Preferably, the base is an organic base or an inorganic base, wherein the organic base is selected from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N-diisopropylethylamine, and / or diisopropylamine; the inorganic base is selected from an alkaline earth metal carbonate or hydroxide; the inert solvent is selected from ethyl acetate, N,N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, dichloromethane, acetonitrile, and / or a polyhalogenated aliphatic hydrocarbon; the reaction is carried out at a temperature of -20°C to 70°C, preferably at a temperature of 45°C to 65°C, for 1 to 8 hours, preferably 2 to 5 hours; when Z is selected from -Cl or -Br, the reaction is carried out in the presence of an alkaline earth metal carbonate, such as potassium carbonate.

[0097] When W is -OH and Z is -OH, the compound represented by formula (II) reacts with the compound represented by formula (III) in the presence of a dehydrating agent and a catalyst in an inert solvent to produce the compound of formula I. Preferably, the dehydrating agent is selected from dicyclohexylcarbodiimide or N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride; the catalyst is selected from N,N-dimethylaminopyridine, sulfuric acid, sulfonic acid, hydrofluoric acid, phosphoric acid, toluenesulfonic acid, polystyrenesulfonate, heteropolyacid, zeolite, metal oxide, graphene oxide, or a combination thereof; the inert solvent is selected from N,N-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, dichloromethane, acetonitrile, and / or polyhalogenated aliphatic hydrocarbons; and the reaction is carried out at a temperature of -20°C to 70°C for 30 minutes to 48 hours.

[0098] When W is -Cl and Z is -OH, the compound represented by formula (II) reacts with the compound represented by formula (III) in the presence of an organic base in an inert solvent to produce the compound represented by formula I. Preferably, the organic base is selected from N,N-dimethylaminopyridine, triethylamine, and / or pyridine; the inert solvent is selected from DMF, tetrahydrofuran, benzene, toluene, dioxane, and / or a halogenated aliphatic hydrocarbon; and the reaction is carried out at a temperature of -20°C to 70°C for 30 minutes to 24 hours, preferably 2 hours to 12 hours.

[0099] When W is -OC(O)R cWhen Z is -OH, the compound of formula (II) reacts with the compound of formula (III) in the presence of a catalyst in an inert solvent to produce a compound of formula I. Preferably, the catalyst is selected from N,N-dimethylaminopyridine, an alkali metal compound catalyst, a Lewis acid catalyst, an alkaline earth metal alkoxide catalyst and / or an organic titanium catalyst; the alkali metal compound catalyst is selected from NaOH, KOH, Li2CO3, Na2CO3, NaHCO3, K2CO3, Na2WO4 or a combination thereof; the Lewis acid catalyst is selected from AlCl3, ZnCl2, SnCl4, TiCl4, FeCl3, MgCl2, Pb(OAc)2, Zn(OAc)2, Al2O(OAc)4 or a combination thereof; the alkaline earth metal alkoxide catalyst is selected from sodium methoxide, sodium ethoxide, magnesium methoxide or a combination thereof; the organic titanium catalyst is selected from butyl titanate Ti(OC4H9)4, dichlorobis(ocene titanate) (Cp2TiCl2) or a combination thereof; the inert solvent is selected from N,N- dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, dichloromethane, acetonitrile and / or polyhalogenated aliphatic hydrocarbon; the reaction is carried out at a temperature of -20°C to 70°C for 30 minutes to 24 hours, preferably 2 hours to 12 hours.

[0100] Explanation of terms:

[0101] Unless otherwise stated, the terms used in the specification and claims have the following meanings:

[0102] The term "alkyl" refers to a saturated aliphatic hydrocarbon radical comprising a straight or branched chain of 1 to 20 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms). An alkyl radical may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate.

[0103] The term "alkenyl" refers to a straight or branched carbon chain comprising from 2 to 20 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms) containing one or more carbon-carbon double bonds.

[0104] The term "alkynyl" refers to a straight or branched carbon chain comprising from 2 to 20 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms) containing one or more carbon-carbon triple bonds.

[0105] The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group having two residues derived from the same or different carbon atoms of an alkane group by removing two hydrogen atoms, preferably a straight or branched chain group containing 1 to 10 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms). When substituted, the substituent may be substituted at any available point of attachment.

[0106] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent, wherein the cycloalkyl group contains 3 to 12 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups.

[0107] The cycloalkyl group may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring that is attached to the parent group is the cycloalkyl group. The cycloalkyl group may be optionally substituted or unsubstituted.

[0108] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that conjugate adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably a 6- to 10-membered ring. Examples of aryl include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indene, and indane.

[0109] The aryl group may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring. The aryl group may be optionally substituted or unsubstituted. Non-limiting examples of fused aryl rings include:

[0110] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and having 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 12 members, more preferably 6 to 10 members, and most preferably 8 to 10 members. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring. Non-limiting examples of heteroaryl groups include:

[0111] Heteroaryl groups can be substituted or unsubstituted.

[0112] The term "substituted" refers to other substituents that are connected to the moiety at any acceptable position of the moiety. Unless otherwise indicated, the moiety can be bonded to carbon, nitrogen, oxygen, sulfur or any other acceptable atom. The substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, -ONO2, cyano, cycloalkyl, heterocyclic radical, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0113] The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0114] In the chemical structure of the compound disclosed herein, It means that there may be multiple optionally substituted carbon units, but each carbon unit is not necessarily the same repeating unit.

[0115] In the chemical structure of the compound disclosed herein, It means that there may be multiple optionally substituted carbon units, but each carbon unit is not necessarily the same repeating unit.

[0116] In the chemical structures of the compounds disclosed herein, the bond No configuration is specified, i.e., the bond Can be or both Two configurations. In the chemical structure of the compound disclosed in the present invention, the bond The configuration is not specified, that is, it can be Z configuration or E configuration, or contain both configurations.

[0117] Although not all of the above structural formulae are drawn in certain isomeric forms for the sake of simplicity, the present disclosure may encompass all isomers, such as tautomers, rotational isomers, geometric isomers, diastereomers, racemates, and enantiomers.

[0118] The aforementioned compounds provided in the present disclosure may exist in the form of pharmaceutically acceptable salts, and the pharmaceutically acceptable salts are selected from: alkali metal salts such as sodium salts or potassium salts; alkaline earth metal salts such as calcium salts; organic base salts such as diethylamine salts, diethanolamine salts, meglumine salts, piperazine salts, and choline salts; inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, hydrofluorides, and hydrobromides; and organic acid salts such as acetates, trifluoroacetates, naphthoates, benzoates, tartrates, lactates, citrates, fumarates, maleates, malates, oxalates, succinates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, naphthalenesulfonates, and camphorsulfonates.

[0119] Compared with the prior art, the present invention has the following beneficial effects:

[0120] 1. The compound of formula I provided by the present invention has improved metabolic characteristics. Its innovative side chain structure gives the compound of formula I a strong cell membrane affinity, thereby endowing the compound with unique diffusion microdynamic properties. After pulmonary administration, it can remain in the local lung for a longer period of time and slowly convert into an effective concentration of treprostinil, significantly increasing the retention time and elimination half-life of treprostinil in the lungs and greatly prolonging the drug's duration of action.

[0121] 2. After pulmonary administration, the compound of formula I provided by the present invention significantly increases the drug concentration ratio of treprostinil in the lungs and plasma, and increases the exposure of treprostinil in the lungs.

[0122] 3. The compound of formula I provided by the present invention can greatly reduce the dosage, provide a lower dosing frequency, a wider therapeutic window, significantly reduce systemic side effects and local adverse reactions in the lungs, and greatly improve the safety of the drug and the patient's tolerance to the drug.

[0123] 4. The compound of formula I provided by the present invention has better physical and chemical properties and stability in solvents, making it easier to make medicine, reducing industrial production costs, and thus is expected to reduce patients' medication costs, which will provide a new treatment option for patients with pulmonary hypertension. BRIEF DESCRIPTION OF THE DRAWINGS

[0124] Figure 1(a). Porcine esterase-mediated hydrolysis conversion of an alkyl ester prodrug compound containing 10 carbon atoms (R-01) and alkyl ester prodrug compounds containing ether bonds with the same number of carbon atoms (R-05, R-06, and R-08).

[0125] Figure 1(b). Porcine esterase-mediated hydrolysis conversion of alkyl ester prodrug compounds (R-09, R-10, R-11) with carboxylate bonds.

[0126] Figure 1(c). Pig esterase-mediated hydrolysis conversion of the compounds of the present invention (Ia-1, Ia-2, Ia-3) and comparative compounds (R-12, C16-TR).

[0127] Figure 2(a). The percentage content of compound Ia-2 in solution samples with different pH values ​​after 5 or 10 days of illumination, where the ratio in brackets on the horizontal axis is the ratio of ethanol to water in the sample solution.

[0128] Figure 2(b). The percentage of compound Ia-2 in solution samples with different pH values ​​after storage at 40°C for 10 or 30 days. The ratio in brackets on the horizontal axis is the ratio of ethanol to water in the sample solution.

[0129] Figure 2(c). The percentage of compound Ia-2 in solution samples with different pH values ​​after storage at 60°C for 10 or 30 days. The ratio in brackets on the horizontal axis is the ratio of ethanol to water in the sample solution.

[0130] Figure 2(d). Percentage of ethyl ester impurity of compound Ia-2 in solutions at different pH values ​​under illumination conditions.

[0131] Figure 2(e). Percentage of ethyl ester impurity of compound Ia-2 in solutions at different pH values ​​under high temperature conditions.

[0132] Figure 3. In vitro IP receptor agonist activity of TRE and treprostinil derivatives (Ia-1, Ia-2, Ia-3).

[0133] Figure 4. Effects of TRE and treprostinil derivatives (Ia-1, Ia-2, Ia-3) on 3 The competitive inhibitory activity of H-PGE2 binding to EP2 receptor, that is, the binding affinity of the compound to EP2 receptor.

[0134] Figure 5. Percent inhibition of U46619-induced increase in right ventricular systolic pressure (RVSP) at various time points after airway aerosol administration of the compounds of the present invention (Ia-1, Ia-2, Ia-3) and comparative compounds (TRE, R-11, R-12, C16-TR). RVSP at 16 h after administration of compound R-12 and 48 h after administration of compound Ia-2 had increased above the basal pressure (indicating that there was no antihypertensive effect), and therefore the relevant data are not shown in the figure.

[0135] Figure 6 shows the percentage inhibition of U46619-induced RVSP elevation 1 hour after airway aerosol administration of low-dose compounds of the present invention (Ia-1, Ia-2, Ia-3) and a control compound (C16-TR). DETAILED DESCRIPTION

[0136] The technical scheme of the present invention will be clearly and completely described below in conjunction with the embodiments. The described embodiments are only used to illustrate the technical scheme of the present invention and are not intended to limit the present invention. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work are within the scope of protection of the present invention. Unless otherwise specified, the reagents and raw materials used in the present invention are commercially available.

[0137] Compound Preparation Examples

[0138] The structures of the compounds were determined by nuclear magnetic resonance ( 1 H NMR) or liquid chromatography-mass spectrometry (LC-MS).

[0139] Liquid chromatography-mass spectrometry (LC-MS) was Agilent 6120; nuclear magnetic resonance (NMR) 1 H NMR) was performed by Bruker Avance-400, and nuclear magnetic resonance ( 1 H NMR) shifts (δ) are given in parts per million (ppm) using d6-DMSO as the solvent and tetramethylsilane (TMS) as the internal standard. Chemical shifts are expressed in 10 -6 The units are given in ppm.

[0140] The term "room temperature" in the present invention refers to a temperature between 10-30°C.

[0141] Comparative Example. Preparation of Compounds R-01, R-03, R-05, R-06, R-08 to R-12

[0142] Treprostinil (500.6 mg, 1.282 mmol) was dissolved in anhydrous DMF (8 mL), and anhydrous potassium carbonate (442.4 mg, 3.201 mmol) and 1-bromodecane (452 ​​mg, 2.044 mmol) were added. The reaction was stirred at 60°C for 3 h. After completion, the mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, and the organic phase was dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (ethyl acetate / n-hexane) to obtain compound R-01 (540.0 mg, 1.018 mmol) in a yield of 79.4%. (MS) ESI [M+Na] +:553.40. HNMR (DMSO-d6, 400MHz) δ0.85 (6H, m); δ0.99-1.10 (2H, m); δ1.10~1.56(25H,m); δ1.56(3H,m); δ1.75(1H,m); δ1.96~2.11(2H,m); δ2.37(2H,m); δ2.71(2H,m); δ3.38(1H,m ;

[0143] Referring to the preparation method of compound R-01, compounds R-03, R-05, R-06, R-08 to R-12 were prepared: Treprostinil (500.6 mg, 1.282 mmol) was dissolved in anhydrous DMF (8 mL), and anhydrous potassium carbonate (442.4 mg, 3.201 mmol) and an appropriate amount (0.9 to 2.0 times the molar amount of treprostinil) of a side chain compound were added. The reaction was stirred at 60°C for 3 h. After completion, the reaction was cooled to room temperature, diluted with ethyl acetate, washed with water, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was then purified by silica gel column chromatography (ethyl acetate / n-hexane) to obtain the respective comparative example compounds. The structures, (MS), ESI, and NMR data of each comparative example compound are as follows:

[0144] Preparation Example 1 Preparation of Compound Ia-1

[0145] Treprostinil (504.0 mg, 1.291 mmol) was dissolved in anhydrous DMF (8 mL), and anhydrous potassium carbonate (445.73 mg, 3.225 mmol) and [4-[(6-bromohexyl)oxy)]-butyl]-benzene (640 mg, 2.051 mmol) were added. The reaction was stirred at 60°C for 3 h. After completion, the reaction was cooled to room temperature, diluted with ethyl acetate, washed with water, and the organic phase dried over anhydrous sodium sulfate. The crude product was then purified by silica gel column chromatography (ethyl acetate / n-hexane) to afford compound Ia-1 (600 mg, 0.964 mmol) in a yield of 74.7%. (MS) ESI [M+H]+: 623.4. HNMR (DMSO-d6, 400MHz) δ0.87 (3H, t); δ1.04~1.62 (26H, m); δ1.76 (1H, m); δ1.95 (1H, m); δ2.11(1H,m); δ2.42(2H,m); δ2.57(2H,t); δ2.71(2H,m); δ3.30(2H,m); δ3.36(3H,m); δ3.47(1H,m); δ4.11( 2H, t); δ4.23 (1H, d); δ4.49 (1H, d); δ4.75 (2H, s); δ6.69~6.75 (2H, d×d); δ7.02 (1H, t); δ7.10~7.30 (5H, m).

[0146] Preparation Example 2 Preparation of Compound Ia-2

[0147] Treprostinil (503.8 mg, 1.290 mmol) was dissolved in anhydrous DMF (8 mL), and anhydrous potassium carbonate (443.3 mg, 3.207 mmol) and [4-[(8-bromohexyl)oxy)]-butyl]-benzene (680 mg, 1.999 mmol) were added. The reaction was stirred at 60°C for 3 h. After completion, the reaction was cooled to room temperature, diluted with ethyl acetate, washed with water, and the organic phase dried over anhydrous sodium sulfate. The crude product was then purified by silica gel column chromatography (ethyl acetate / n-hexane) to afford compound Ia-2 (550 mg, 0.846 mmol) in a yield of 65.5%. (MS) ESI [M+Na]+: 673.4. HNMR (DMSO-d6, 400MHz) δ0.86 (3H, t); δ0.96~1.67 (30H, m); δ1.76 (1H, m); δ 1.95 (1H, m); δ2.11 (1H, m); δ2.41 (2H, m); δ2.58 (2H, t); δ2.68 (2H, m); δ3.30 (2H, m); δ3.36 (3H, m); δ3.47 (1H, m); δ4.09 (2H, t); δ4.23 (1H, d); δ4.49 (1H, d); δ4.75 (2H, s); δ6.73 (2H, dd); δ7.03 (1H, t); δ7.18 (3H, m); δ7.27 (2H, t).

[0148] Preparation Example 3 Preparation of Compound Ia-3

[0149] Treprostinil (505.1 mg, 1.293 mmol) was dissolved in anhydrous DMF (8 mL), and anhydrous potassium carbonate (448.4 mg, 3.244 mmol) and [4-[(10-bromohexyl)oxy)]-butyl]-benzene (700 mg, 1.895 mmol) were added. The reaction was stirred at 60°C for 3 h. After completion, the reaction was cooled to room temperature, diluted with ethyl acetate, washed with water, and the organic phase dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give compound Ia-3 (600 mg, 0.884 mmol) in a yield of 68.4%. (MS) ESI [M+Na]+: 701.4. HNMR (DMSO-d6, 400MHz) δ0.86 (3H, t); δ0.96~1.67 (34H, m); δ1.76 (1H, m); δ 1.95 (1H, m); δ2.10 (1H, m); δ2.42 (2H, m); δ2.58 (2H, t); δ2.71 (2H, m); δ3.30 (2H, m); δ3.36 (3H, m); δ3.48 (1H, m); δ4.09 (2H, t); δ4.24 (1H, d); δ4.48 (1H, d); δ4.75 (2H, s); δ6.73 (2H, dd); δ7.03 (1H, t); δ7.19 (3H, m); δ7.25 (2H, t).

[0150] The following compounds were synthesized using a similar procedure as described above:

[0151] Preparation Example 4 Preparation of Compound Ia-18

[0152] (1) Preparation of the intermediate compound (2-((6-bromohexyl)oxy)ethoxy)methyl)benzene

[0153] Sodium hydride (0.984 g, 0.0246 mol) was dissolved in anhydrous THF (30 mL), and 1,6-dibromohexane (12 g, 0.0492 mol) was slowly added. Under N2 protection, the mixture was stirred for 30 min, and then 2-benzyloxyethanol (2.5 g, 0.0164 mol) was added. The mixture was refluxed at 75°C overnight. After cooling, the sodium hydride was quenched by water, the mixture was diluted with ethyl acetate, and the mixture was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:90) to obtain the compound (2-((6-bromohexyl)oxy)ethoxy)methyl)benzene (2.6963 g, 0.00855 mol) in a yield of 52.2%. 1H NMR (500MHz, CDCl3): δ7.37-7.27(m,5H),4.58(s,2H),3.61(s,4H),3.47(t,J=6.6Hz,2H ),3.40(t,J=6.8Hz,2H),1.86(p,J=6.9Hz,2H),1.61(p,J=6.8Hz,2H),1.50-1.33(m,4H).

[0154] (2) Preparation of Compound Ia-18

[0155] Treprostinil (522.20 mg, 1.337 mmol) was dissolved in anhydrous DMF (5 mL), and anhydrous potassium carbonate (501.71 mg, 3.630 mmol) and (2-((6-bromohexyl)oxy)ethoxy)methyl)benzene (479.8 mg, 1.402 mmol) were added. The reaction was stirred at 60°C for 3 h. After completion, the reaction was cooled to room temperature, diluted with ethyl acetate, washed with water, and the organic phase dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / n-hexane) to obtain compound Ia-18 (800 mg, 1.281 mmol) in a yield of 95.8%. (MS) ESI [M+Na]+: 647.0. 1 HNMR (CDCl3-d6, 400MHz); δ0.92 (3H, d); δ1.10~1.75 (22H, m); δ1.91 (1H, m); δ2.22 (2H, m); δ2.35-2.47 (2H, m); δ2.76-2.91 (2H, m); δ3.48 (2H, t); δ3.63 (5H, t); δ3.77 (1H, m); δ4.20 (2H, m); δ4.61 (4H, d); δ6.63 (1H, t); δ6.83 (1H, d); δ7.07 (1H, m); δ7.28-7.36 (5H, m) Preparation Example 5 Preparation of Compound Ia-19

[0156] (1) Preparation of the intermediate compound 2-((2-((6-bromohexyl)oxy)ethoxy)methyl)-1,3-dichlorobenzene

[0157] Sodium hydride (0.678 g, 0.0169 mol) was dissolved in anhydrous THF (30 mL), and 1,6-dibromohexane (8.27 g, 0.0339 mol) was slowly added. Under N2 protection, the mixture was stirred for 30 min, and then 2-((2,6-dichlorobenzyl)oxy)ethanol (2.5 g, 0.0113 mol) was added. The mixture was refluxed at 75°C overnight. After cooling, the sodium hydride was quenched by water, the mixture was diluted with ethyl acetate, and the mixture was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:200) to obtain the compound 2-((2-((6-bromohexyl)oxy)ethoxy)methyl)-1,3-dichlorobenzene (2.8103 g, 0.00732 mol) in a yield of 64.7%. 1 H NMR (500MHz, CDCl3): δ7.31(d,J=8.0Hz,2H),7.18(dd,J=8.5,7.5Hz,1H),4.83(s,2H),3.70(dd,J=5.9,3.9Hz,2H),3.61(dd, J=5.8,4.0Hz,2H),3.46(t,J=6.6Hz,2H),3.40(t,J=6.9Hz,2H),1.85(p,J=7.0Hz,2H),1.62-1.56(m,2H),1.48-1.35(m,4H).

[0158] (2) Preparation of Compound Ia-19

[0159] Treprostinil (518.57 mg, 1.328 mmol) was dissolved in anhydrous DMF (5 mL), and anhydrous potassium carbonate (278.92 mg, 2.018 mmol) and 2-((2-((6-bromohexyl)oxy)ethoxy)methyl)-1,3-dichlorobenzene (457.16 mg, 1.115 mmol) were added. The reaction was stirred at 60°C for 3 h. After completion, the reaction was cooled to room temperature, diluted with ethyl acetate, washed with water, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / n-hexane) to obtain compound Ia-19 (800 mg, 1.155 mmol) in an 86.9% yield. (MS) ESI [M+Na]+: 714.8. HNMR (CDCl3-d6, 400MHz) δ0.92 (3H, t) δ1.28-1.68 (22H, m); δ1.90 (1H, m); δ 2.23 (2H, m); δ2.49 (1H, m); δ2.58 (1H, m); δ2.77 (1H, m); δ2.89 (1H, m); δ3.47 (2H, t); δ3.62 (3H, m); δ3.75 (3H, m); δ4.20 (2H, t); δ4.63 (2H, s); δ4.85 (2H, ss); δ6.66 (1H, d); δ6.83 (1H, d); δ7.08 (1H, t); δ7.19 (1H, t); δ7.32 (2H, m).

[0160] Experimental part

[0161] Experimental Example 1: Study on the hydrolysis conversion rate of compounds mediated by pig esterase

[0162] The compound provided by the present invention can be hydrolyzed into the active ingredient Treprostinil (TRE) under the action of esterase. The purpose of this experiment is to evaluate the conversion rate of compounds with different ester side chain structures to TRE under the action of esterase.

[0163] According to patent document CN105848479B, the hydrolysis rate of TRE alkyl ester prodrug compounds under esterase is related to the carbon chain length of the ester side chain. When the alkyl side chain has 8 or fewer carbon atoms, the prodrug compound is 100% converted to TRE within 30 minutes under esterase. However, when the carbon number exceeds 8, the conversion rate of the prodrug to TRE is significantly slowed.

[0164] Experiment (a) evaluated the hydrolysis conversion of compounds containing ether-bound alkyl ester side chains.

[0165] Weigh 20 mg of each comparative example compound R-01, R-05, R-06, and R-08. The ester side chain of each compound has 10 carbon atoms, and the alkyl side chains of R-05, R-06, and R-08 contain 1 to 3 oxygen atoms, respectively. Dissolve them in 20 mL of ethanol to prepare a 1 mg / ml test compound solution for use. Pipette 1 mL of the test compound solution into 4 mL of PBS aqueous solution to obtain a 0.2 mg / mL test compound reaction solution. Add 20 U (80 μL) of porcine esterase, shake well, and incubate at 38°C. After a period of reaction, take samples at 10 min, 30 min, 1 hr, and 2 hr to detect the conversion of the test compound to TRE. For each sample, calculate the hydrolysis rate based on the measured reactant and product peak areas:

[0166] % hydrolysis = product peak area / (reactant peak area + product peak area) * 100%

[0167] The experimental results are shown in Figure 1(a). The results show that the insertion of an oxygen atom into the alkyl side chain of the prodrug compound significantly accelerates the conversion rate of the prodrug compound to TRE.

[0168] Experiment (b) evaluated the hydrolysis conversion of compounds containing alkyl ester side chains.

[0169] The hydrolysis conversion rates of comparative compounds R-09, R-10, and R-11 were measured using the method described in Experiment (a). Sampling was performed at 20 minutes, 40 minutes, 1 hour, and 2 hours. The results are shown in Figure 1(b). The results indicate that hydrolysis of each compound was nearly complete at 40 minutes. When the fatty side chain contained a carboxylate structure, increasing the carbon number did not increase the conversion rate of the compound to TRE. Even increasing the steric hindrance around the ester bond connecting the side chain to the TRE did not significantly increase the conversion rate.

[0170] Experiment (c) evaluated the hydrolysis conversion of the compounds provided by the present invention and the comparative compounds.

[0171] The hydrolysis conversion rates of compounds Ia-1, Ia-2, Ia-3, C16-TR, R-09, and R-12 of the present invention were measured using the method described in experiment (a). Sampling time points were 5 minutes, 15 minutes, 30 minutes, 1 hour, and 2 hours. The experimental results are shown in Figure 1(c). The results demonstrate that, like C16-TR, the compounds of the present invention significantly prolong the hydrolysis conversion rate, slowly and steadily releasing TRE. This, to some extent, also reflects that the compounds of the present invention can increase the elimination half-life of treprostinil in the lungs. Furthermore, the hydrolysis rate slows as the number of carbon atoms in the ester side chain of the compounds of the present invention increases.

[0172] Experimental Example 2: Study on the Stability of Treprostinil Derivatives in Ethanol

[0173] This experimental example is used to evaluate the stability of the treprostinil derivative of the present invention in ethanol.

[0174] Prepare 100 mL of 1 mol / L hydrochloric acid and / or sodium hydroxide aqueous solution with distilled water at different pH values ​​(3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, and 10.0) for later use. Weigh 640 mg of compound Ia-2 and dissolve it completely in 640 mL of 90% ethanol as a diluent to create a 1 mg / mL sample solution 1 for later use.

[0175] (1) 40 mL of 90% ethanol was measured, and 80 mL of sample solution 1 and aqueous solutions of different pH values ​​(3.0, 5.0, 7.0, and 9.0) were uniformly mixed (ethanol:water = 1.5:1). The samples were then filled into tubes (2 mL each), for a total of 90 samples, which were divided into three groups for stability testing after exposure to light, high temperature (40°C), and high temperature (60°C). The samples in the two high-temperature testing groups were packaged in aluminum foil bags, 10 pieces per bag; the samples in the light stability testing group were packaged in transparent bags, 10 pieces per bag.

[0176] (2) 80 mL of 90% ethanol was measured and mixed evenly with 80 mL each of sample solution 1 and aqueous solutions of different pH values ​​(4.0, 6.0, 8.0, and 10.0) (ethanol:water = 2:1). The mixture was then filled, grouped, and packaged as above.

[0177] After the samples were placed under the conditions described in Table 1, 15 samples were drawn from each pH solution group at each testing time point for testing, including compound content, related substance (impurity) content, and liquid properties (whether there was turbidity, stratification, or color change). The compound and related substance content was calculated using the area normalization method to calculate the percentage of the area occupied by the main component.

[0178] Table-1 Storage conditions for stability study of compound Ia-2

[0179] The specific results of this experiment are shown in Figure 2. The results in Figures 2a-c demonstrate that the compounds provided by the present invention are stable in high-concentration ethanol solutions with different pH values ​​(ethanol:water = 1.5:1, ethanol:water = 2.0:1), with the content remaining above 95% after 10 days. Even after 30 days at 40°C, the content of compound Ia-2 in each group remained above 80%. After 30 days at 60°C, the content of compound Ia-2 in solutions with a pH of 5.0-9.0 remained above 90%, a very exciting result.

[0180] According to the document CN105848479B and Adam J. Plaunt, et al. (2021), C16-TR cannot be dissolved in HFA propellant when the ethanol content is lower than 13%, and DSPE-PEG2000 must be added to assist solubility. It cannot maintain solubility during long-term storage (>1 week), that is, it exhibits poor physical stability (precipitation rings appear at the gas-liquid interface, free-floating insoluble substances are observed, etc.), and ester-substituted impurities with alcohol solvents appear. Surprisingly, the compounds provided by the present invention have good solubility in ethanol and can be completely dissolved in 8% ethanol without the need for additional co-solvents; in the study of various influencing factors (light, high temperature, strong acid and strong base) in this experimental example, the compounds of the present invention all exhibited good solubility (all clear liquids) and stability. As shown in Figures 2d-e, under light conditions, the ethyl ester impurities formed in each group after 10 days of storage were all less than 1.80%. When placed at high temperature for a long time, only under extreme conditions (pH = 3, 60°C for 30 days; pH = 10, 40°C for 30 days or 60°C for more than 10 days) will about 8.0-9.0% of ethyl ester impurities be formed. Under other conditions, the amount of ethyl ester impurities is less than 4.0%.

[0181] Experimental Example 3: In vitro agonist activity of treprostinil derivatives on IP receptors

[0182] The agonist activity of the compounds of the present invention (Ia-1, Ia-2, Ia-3) on IP receptors was tested by FLIPR assay for detecting calcium ions, and compared with compound TRE.

[0183] a) Cell preparation:

[0184] The IP / HEK293 cell line was provided by Shanghai WuXi AppTec Pharmaceutical Development Co., Ltd. The well-grown IP / HEK293 cells were removed from the incubator, the culture medium was aspirated, and after rinsing with D-PBS and digesting with trypsin-EDTA, cell culture medium was added and the cells were fully suspended by continuous aspiration. Centrifugation was performed at room temperature, the supernatant was aspirated, the culture medium was added, and the cells were resuspended by continuous aspiration using a sterile pipette. TM After counting the living cells, 20 μL (20,000 cells / well) of cell suspension was added to each well of a 384-well cell culture plate and incubated in a 37° C. 5% CO 2 incubator overnight.

[0185] b) Prepare FLIPR reagent:

[0186] Add 77 mg of probenecid to 1 mL of FLIPR assay buffer to make a 250 mM probenecid solution. Thaw a bottle of 2X Fluo-4 Direct™ (F10471) and add 10 mL of FLIPR assay buffer containing 500 μM AEBSF. Add 0.2 mL of probenecid per 10 mL of Fluo-Direct to a final concentration of 2.5 mM. Vortex and let stand in the dark for at least 5 minutes.

[0187] c) Prepare the compound:

[0188] The compounds were placed in a 25°C water bath for 30 minutes. These compounds were then serially diluted 10-fold using Bravo for a total of 10 concentrations for testing. Using ECHO, 750 nL of compound was transferred to a 384-well compound plate. 30 μL of assay buffer was then added to the plate.

[0189] d) Test steps:

[0190] Remove the 384-well cell culture plate from the incubator, discard the culture medium, and use a pipette to add 20 μl of assay buffer and 20 μl of 2X Fluo-4 Direct™ No-Wash Loading Buffer. Incubate in a 37°C, 5% CO2 incubator for 50 minutes, followed by 10 minutes at room temperature. Place the cell culture plate, compound plate, and tip box into the FLIPR. Run the FLIPRTETRA assay program, pipette 10 μl of the reference compound and test compound from the compound plate onto the cell culture plate, read the fluorescence signal, and perform data processing. Analyze the data using Prism.

[0191] The specific test results are shown in Figure 3. As can be seen from the figure, compound TRE has strong agonist activity on the target IP receptor and is concentration-dependent. However, compounds Ia-1, Ia-2, and Ia-3 provided by the present invention, as prodrug compounds, have no agonist effect on the target IP receptor at various concentrations, demonstrating the safety of the compounds of the present invention as prodrug compounds.

[0192] Experimental Example 4: In vitro affinity test of treprostinil derivatives for EP2 receptors

[0193] This experiment was carried out in a 96-well plate by testing the compounds of the present invention (Ia-1, Ia-2, Ia-3) with radiolabeled ligands. 3 The ability of H-PGE2 to competitively bind to the prostaglandin EP2 receptor was used to evaluate the binding affinity of the compounds of the present invention to the EP2 receptor. Treprostinil was used as a control. The captured 3 H number, and Prism software was used for data analysis.

[0194] EP2 membrane (Merck, Cat#HTS185M, lot number 2121326) was diluted with buffer (50 mM Hepes, pH=7.4, 5 mM MgCl2, 1 mM CaCl2, 0.5% BSA) to a final concentration of 75 μg / ml. 3 H-PGE2 was diluted to 15 nM. Test compound and control compound solutions were prepared with a starting concentration of 10 μM and serially diluted 10-fold for a total of 8 concentrations for testing. 5% DMSO was used as the solvent control.

[0195] 1 μL of different compound solutions were added to the corresponding positions in the 96-well test plate, and 50 μL of EP2 membrane was added to each well (about 3.75 μg / well). 3 H-PGE2 50uL. Then seal the plate and incubate at room temperature with a shaker at 300rpm for 2 hours. After incubation, filter the GF / C plate with Perkin Elmer Filtermate Harvester, and then wash each plate 4 times with cold eluent. Dry at 50℃ for 1 hour. After drying, seal the bottom of the filter plate wells with Perkin Elmer unifilter-96 backing tape. Add 50μl Perkin Elmer Microscint O. Seal the top of the filter plate with Perkin Elmer TopSeal-A sealing membrane. Detect the captured 3 H number.

[0196] The specific experimental results are shown in Figure 4. 3 The competitive binding of H-PGE2 to its target EP2 receptor is concentration-dependent. This indicates that its binding to the target EP2 receptor increases with increasing TRE concentration. However, compounds Ia-1, Ia-2, and Ia-3, as prodrug compounds, do not bind to the target EP2 at any concentration, demonstrating the safety of the compounds of the present invention as prodrugs.

[0197] Experimental Example 5: Study on the efficacy of each compound after airway aerosol administration in the rat model of acute pulmonary artery pressure elevation induced by U46619

[0198] 1. Experimental purpose:

[0199] U46619 is a stable analog of thromboxane A2 (TXA2). By binding to the thromboxane A2 receptor, it activates downstream IP3 signaling, promoting vasoconstriction and platelet aggregation. Using a U46619-induced pulmonary artery hypertension model in rats, the effects of airway aerosol administration of compound C16-TR and equimolar amounts of compounds Ia-1, Ia-2, Ia-3, R-11, and R-12 on pulmonary hypertension in rats at different times were studied. The effects were compared with airway aerosol administration of an equimolar amount of TRE.

[0200] 2. Experimental Materials

[0201] 2.1 Main instruments

[0202] MP160 16-channel physiological recorder, rat aerosol pulmonary drug delivery device / endotracheal drug delivery device, rat laryngoscope, small animal anesthesia machine, syringe, mouse fixator, etc.

[0203] 2.2 Main reagents

[0204] Dimethyl sulfoxide, PBS, methyl acetate, sodium chloride solution, 10% urethane, isoflurane, heparinized saline. Modeling reagent: U46619 (9,11-dideoxy-11A,9A-methyleneepoxyprostaglandin F2A).

[0205] 2.3 Experimental animals

[0206] Thirty-four SPF male SD rats weighing approximately 250-400 g were used.

[0207] 2.4 Preparation of test samples

[0208] Test sample preparation: Weigh the required amount of compound TRE into a sterile EP tube. Add an appropriate amount of DMSO to each tube to dissolve to a stock solution (100 mg / ml). Dissolve compounds C16-TR, Ia-1, Ia-2, Ia-3, R-11, and R-12 in their original bottles in an appropriate amount of DMSO to prepare a stock solution (100 mg / ml) and transfer to sterile EP tubes. Store these stock solutions in a sealed container at 4°C, protected from light. When testing, transfer an appropriate amount of the stock solution to a new sterile EP tube and dilute with DMSO and 1× PBS to the target concentration of 3% DMSO / 1× PBS (working solution).

[0209] Preparation of modeling preparation: Take 900 μL of methyl acetate and add it to the original bottle of U46619, mix well and prepare a 1 mg / ml (1 μg / μL) stock solution, dispense 10 μL (1 μg / μL) into sterile EP tubes and store in a -20°C refrigerator; on the day of modeling, remove the stock solution, equilibrate it to room temperature, and add an appropriate amount of 0.9% sodium chloride solution (sterile) to each tube for 20-fold dilution to prepare a working solution with a concentration of 50 ng / μl.

[0210] 2.5 Animal grouping and drug administration

[0211] The airway aerosolized doses of compound TRE and each test compound were equimolar based on TRE. The doses for the compound TRE group (n=3) were 13.3 μg / kg, the compound C16-TR group (n=5) was 20.9 μg / kg, the compound Ia-1 group (n=3) was 21.2 μg / kg, the compound Ia-2 group (n=6) was 22.1 μg / kg, the compound Ia-3 group (n=6) was 23.1 μg / kg, the compound R-11 group (n=3) was 21.9 μg / kg, and the compound R-12 group (n=3) was 21.7 μg / kg. There were also model control groups (n=1) and solvent control groups (n=3).

[0212] U46619 (25 μg / kg) was injected into the left jugular vein of rats at various time points after airway aerosol administration. The peak RVSP elevation reached after U46619 injection was recorded and compared with the baseline RVSP value to calculate the percentage inhibition of RVSP elevation. In the model control group, U46619 was administered intravenously immediately after successful basal RVSP measurement by catheterization. The time points for intravenous U46619 administration in the remaining test compound groups are shown in Table 2. All animals underwent right cardiac catheterization to measure RVSP and undergo gross respiratory assessment.

[0213] Table-2 Time points of administration of U46619 in each group

[0214] 2.6 Results

[0215] 2.6.1 General Observation Results

[0216] Under the experimental conditions, except for the model control group, all SD rats in the group were anesthetized with isoflurane and immediately received airway aerosol drug administration. No respiratory abnormalities were observed after drug administration.

[0217] 2.6.2 Right ventricular systolic pressure (RVSP) results

[0218] Each test compound exhibited an inhibitory effect on U46619-induced RVSP elevation. Based on the literature referenced by Richard W. Chapman, et al. (2018 Pulmonary Pharmacology & Therapeutics), the critical threshold for compound efficacy was set at a 30% inhibition of RVSP elevation. The percentage inhibition of U46619-induced RVSP elevation in each group of experimental animals at various time points is shown in Figure 5.

[0219] As shown in Figure 5(a), RVSP of the two control compounds R-11 and R-12 had returned to or above baseline pressure 6 hours after nebulized administration, indicating that the compounds had essentially no antihypertensive effect. In contrast, Figure 5(b) shows that both the compounds provided by the present invention and the control compound C16-TR exhibited long-lasting antihypertensive effects. Compound Ia-1 exhibited superior antihypertensive effects to C16-TR at 1 and 6 hours, but similar to C16-TR, exhibited no antihypertensive effect at 16 hours. Compounds Ia-2 and Ia-3 exhibited similar long-lasting effects, and their antihypertensive effects were stronger and longer-lasting than those of C16-TR, with significant antihypertensive effects still observed at 24 hours.

[0220] Experimental Example 6: Pharmacological Effects of Low-Dose Compound C16-TR and Test Compounds on U46619-Induced Acute Increase in Pulmonary Artery Pressure in Rats by Airway Atomization

[0221] 1. Experimental purpose:

[0222] The airway aerosol administration dose of each compound in this experiment was approximately 1 / 7 of the airway aerosol administration dose in Experimental Example 5. The U46619-induced acute pulmonary artery pressure elevation model in rats was used to further verify the antihypertensive effect of the compounds of the present invention after airway aerosol administration by reducing the administration dose.

[0223] 2. Animal grouping and drug administration:

[0224] The model construction method was the same as that described in Experimental Example 5. In this experiment, the dosages of each group were as follows: the compound C16-TR group was 3 μg / kg, and the equimolar dosages of compounds Ia-1, Ia-2, and Ia-3 were 3.0 μg / kg, 3.2 μg / kg, and 3.3 μg / kg, respectively.

[0225] Anesthetized SD rats were administered the drug via airway aerosol. Baseline right ventricular systolic pressure (RVSP) was then measured using right cardiac catheterization. One hour after airway aerosol administration of each compound, U46619 (25 μg / kg) was administered intravenously. The peak RVSP elevation after U46619 injection was recorded and compared with the baseline RVSP value to calculate the percentage inhibition of the RVSP elevation. One to two animals were used in each group.

[0226] 3. Experimental results

[0227] The results of this experiment, as shown in Table 3 and Figure 6, show that even with a 7-fold dose reduction, the compound of the present invention still significantly lowered blood pressure (i.e., inhibited the U46619-induced RVSP elevation) 1 hour after airway aerosol administration. This antihypertensive effect was even stronger than the antihypertensive effect of 13.3 μg / kg of TRE administered via airway aerosol 16 minutes after a 16-minute dose in Experimental Example 5 (the percentage inhibition of RVSP elevation was approximately 39%). This is an exciting result. In contrast, the control compound, C16-TR, had no antihypertensive effect at this time. This suggests that the compound of the present invention is more effectively converted to TRE, with a faster onset of action and a stronger antihypertensive effect.

[0228] Table-3 Inhibition percentage of RVSP elevation after 1 hour of airway aerosol administration of low-dose test compounds

[0229] The above experimental results show that the compounds provided by the present invention can be effectively converted into TRE to exert a hypotensive effect after pulmonary administration. Compared with the control compound, the unique side chain structure of the compound of the present invention gives the compound a stronger affinity for lung tissue and unique local diffusion microdynamic characteristics, which enables the compound of the present invention to exert a long-lasting pharmacodynamic effect as a prodrug while also having the excellent effect of rapid onset. It indicates that after pulmonary administration, the compound of the present invention can significantly reduce the dosage of the drug, reduce adverse reactions caused by systemic drug exposure, and at the same time reduce the risk of pulmonary adverse reactions such as coughing caused by local excessive concentration of active ingredients; its long-lasting and effective antihypertensive effect can reduce the frequency of administration, providing patients with pulmonary hypertension with a more effective, more convenient and better tolerated treatment option, and therefore has far-reaching clinical value and advantages.

[0230] Although the present application has been described with reference to specific embodiments thereof, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the present application. In addition, various modifications may be made to adapt specific circumstances, materials, substances, methods, and combinations of method steps to the objective spirit and scope of the present disclosure. All such modifications are intended to be within the scope of the appended claims.

[0231] The contents of all patents, patent applications, and journal articles cited in this application are incorporated by reference in their entirety for all purposes.

Claims

1. A compound represented by formula I, an isomer thereof or a pharmaceutically acceptable salt thereof, in, Each X is independently selected from O or S; A is a cyclic group, and the cyclic group is selected from phenyl, 5- to 10-membered heteroaryl, wherein the heteroatom in the 5- to 10-membered heteroaryl is selected from one or more of N, O, and S; R 1 , R 2 Each is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, hydroxyl, amino, cyano, nitro, or -ONO2, or R 1 , R 2 Together with the carbon atoms to which they are attached, they form a cyclic group, wherein the C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy is optionally substituted by one or more substituents selected from the following groups: cycloalkyl, aryl, heteroaryl, -NR 3 R 4 , halogen atoms, hydroxyl, cyano, thiol, nitro or -ONO2; R 3 , R 4 Each is independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, or R 3 and R 4 Together with the nitrogen atom to which they are attached, they form a 5-8 membered heterocyclic ring; Each Y is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, carboxyl, cyano, thiol, C1-C6 alkoxy, C1-C6 alkylamino, or 3-8 membered cycloalkyl; m is an integer from 4 to 16; n is an integer from 0 to 8; j is an integer from 0 to 2; k is an integer from 0 to 3.

2. The compound according to claim 1, its isomer or a pharmaceutically acceptable salt thereof, wherein: The A is a phenyl group.

3. The compound according to claim 1 or 2, its isomer or a pharmaceutically acceptable salt thereof, wherein: Each X is independently O.

4. The compound according to any one of claims 1 to 3, its isomer or a pharmaceutically acceptable salt thereof, wherein: The R 1 and R 2 Each independently selected from H or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted by one or more substituents selected from the group consisting of halogen atoms, hydroxyl groups, cyano groups, amino groups, nitro groups, -ONO2 groups, and mercapto groups.

5. The compound, isomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein each Y is independently selected from C1-C6 alkyl, halogen, cyano, or C1-C6 alkoxy.

6. The compound according to any one of claims 1 to 3, its isomer or a pharmaceutically acceptable salt thereof, wherein each Y is independently chlorine. 7 . The compound according to claim 1 , its isomer or a pharmaceutically acceptable salt thereof, wherein m is an integer from 6 to 10. 8 . The compound according to claim 1 , its isomer or a pharmaceutically acceptable salt thereof, wherein n is an integer of 4 to 6. 9 . The compound according to claim 1 , its isomer or a pharmaceutically acceptable salt thereof, wherein j is an integer from 0 to 1. 10 . The compound, its isomer or pharmaceutically acceptable salt thereof according to claim 1 , wherein k is an integer from 0 to 2.

11. A compound, an isomer thereof or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

12. An isotope substituted product of the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein the isotope substituted product is preferably a deuterium atom substituted product.

13. A pharmaceutical composition comprising the compound of formula I according to any one of claims 1 to 11, its isomer or a pharmaceutically acceptable salt thereof, or the isotope substitution according to claim 12, and a pharmaceutically acceptable excipient.

14. Use of the compound according to any one of claims 1 to 11, its isomer or pharmaceutically acceptable salt thereof, the isotope substitution according to claim 12, or the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating pulmonary hypertension.

15. Use of the compound according to any one of claims 1 to 11, its isomer or pharmaceutically acceptable salt thereof, the isotope substitution according to claim 12, or the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating pulmonary fibrosis.

16. The use according to claim 14 or 15, comprising administering to a patient in need thereof an effective amount of the compound according to any one of claims 1 to 11, its isomer or pharmaceutically acceptable salt thereof, or the isotope substitution according to claim 12, or the pharmaceutical composition according to claim 13.

17. The use according to claim 16, wherein the drug is administered via the lungs.

18. The use according to claim 17, wherein pulmonary administration comprises administration via a metered dose inhaler, a dry powder inhaler, a nebulizer, a soft mist inhaler.

19. The use according to claim 17, wherein pulmonary administration comprises administration via a metered dose inhaler.

20. The use of claim 17, wherein pulmonary administration comprises administration via a dry powder inhaler.

21. The use according to claim 17, wherein pulmonary administration comprises administration via an aerosol nebulizer.

22. The use according to claim 17, wherein pulmonary administration comprises administration via a soft mist inhaler.

23. The use according to claim 14, wherein the patient suffering from pulmonary hypertension is a World Health Organization Group I pulmonary hypertension patient.

24. The use according to claim 14, wherein the patient suffering from pulmonary hypertension is a World Health Organization Group II pulmonary hypertension patient.

25. The use according to claim 14, wherein the patient suffering from pulmonary hypertension is a World Health Organization Group III pulmonary hypertension patient.

26. The use according to claim 14, wherein the patient suffering from pulmonary hypertension is a World Health Organization Group IV pulmonary hypertension patient.

27. The use according to claim 14, wherein the patient suffering from pulmonary hypertension is a World Health Organization Group V pulmonary hypertension patient.

28. The method of claim 14, wherein the pulmonary hypertension is selected from pulmonary arterial hypertension, pulmonary hypertension caused by left heart disease, pulmonary hypertension caused by lung disease and / or hypoxia, chronic thromboembolic pulmonary hypertension, pulmonary hypertension caused by pulmonary artery obstructive lesions, and pulmonary hypertension associated with systemic or metabolic diseases.

29. The use according to claim 28, wherein the pulmonary hypertension is selected from idiopathic pulmonary hypertension, hereditary pulmonary hypertension, congenital heart disease-related pulmonary hypertension, and portal hypertension-related pulmonary hypertension.

30. The use according to claim 28, wherein the pulmonary hypertension is idiopathic pulmonary hypertension.

31. The use according to claim 28, wherein the pulmonary hypertension is hereditary pulmonary hypertension.

32. The use according to claim 28, wherein the pulmonary hypertension is pulmonary hypertension caused by left heart disease.

33. The use according to claim 28, wherein the pulmonary hypertension is pulmonary hypertension caused by lung disease and / or hypoxia.

34. The use according to claim 33, wherein the pulmonary hypertension caused by the lung disease and / or hypoxia is selected from pulmonary hypertension associated with interstitial lung disease, pulmonary hypertension caused by chronic obstructive pulmonary disease, and pulmonary hypertension caused by pulmonary fibrosis combined with emphysema.

35. The use according to claim 28, wherein the pulmonary hypertension is chronic thromboembolic pulmonary hypertension.

36. The use according to claim 28, wherein the pulmonary hypertension is pulmonary hypertension associated with systemic or metabolic diseases.

37. The use according to claim 36, wherein the systemic or metabolic disease-associated pulmonary hypertension is sarcoidosis-associated pulmonary hypertension.

38. The use according to claim 15, wherein the pulmonary fibrosis disease is selected from pulmonary interstitial fibrosis caused by idiopathic interstitial pneumonia and pulmonary interstitial fibrosis caused by connective tissue disease.

39. The use according to claim 38, wherein the pulmonary interstitial fibrosis caused by idiopathic interstitial pneumonia is idiopathic fibrosis.

40. The use according to any one of claims 14, 15, 17-22, wherein An effective amount of a compound of formula I, an isomer or a pharmaceutically acceptable salt thereof is administered to the patient once daily.

41. The use according to any one of claims 14, 15, 17-22, wherein An effective amount of a compound of formula I, an isomer or a pharmaceutically acceptable salt thereof is administered to the patient once every two days.

42. The use according to any one of claims 14, 15, 17-22, wherein An effective amount of a compound of formula I, an isomer or a pharmaceutically acceptable salt thereof is administered to the patient twice daily.

43. A method for preparing a compound of formula I as described in any one of claims 1 to 11, comprising the following steps: The compound of formula II is reacted with the compound of formula III to produce the compound of formula I in, W is -OH, -Cl or -OC(O)R c , where R c is a C1-C5 alkyl group; Wherein, Z is selected from -OH, -Cl, -Br, -I; Y, A, R 1 , R 2 , X, n, j, m and k are as defined in claim 1.

44. The method of claim 43, wherein: When W is -OH and Z is selected from -Cl, -Br, -I, the compound of formula (II) reacts with the compound of formula (III) in the presence of a base in an inert solvent to produce the compound of formula I.

45. The method of claim 44, wherein: The base is an organic base or an inorganic base, wherein the organic base is selected from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N-diisopropylethylamine and / or diisopropylamine; the inorganic base is selected from alkaline earth metal carbonates or hydroxides; the inert solvent is selected from ethyl acetate, N,N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, dichloromethane, acetonitrile and / or polyhalogenated aliphatic hydrocarbons; the reaction is carried out at a temperature of -20°C to 70°C, preferably at a temperature of 45°C to 65°C, for 1 to 8 hours, preferably 2 to 5 hours; when Z is selected from -Cl or -Br, the reaction is carried out in the presence of an alkaline earth metal carbonate such as potassium carbonate.

46. ​​The method of claim 43, wherein: When W is -OH and Z is -OH, the compound represented by formula (II) reacts with the compound represented by formula (III) in the presence of a dehydrating agent and a catalyst in an inert solvent to produce a compound represented by formula I.

47. The method of claim 46, wherein: The dehydrating agent is selected from dicyclohexylcarbodiimide or N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride; the catalyst is selected from N,N-dimethylaminopyridine, sulfuric acid, sulfonic acid, hydrofluoric acid, phosphoric acid, toluenesulfonic acid, polystyrene sulfonate, heteropolyacid, zeolite, metal oxide, graphene oxide or a combination thereof; the inert solvent is selected from N,N-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, dichloromethane, acetonitrile and / or polyhalogenated aliphatic hydrocarbons; the reaction is carried out at a temperature of -20°C to 70°C for 30 minutes to 48 hours.

48. The method of claim 43, wherein: When W is -Cl and Z is -OH, the compound represented by formula (II) reacts with the compound represented by formula (III) in the presence of an organic base in an inert solvent to produce the compound represented by formula I.

49. The method of claim 48, wherein: The organic base is selected from N,N-dimethylaminopyridine, triethylamine and / or pyridine; the inert solvent is selected from DMF, tetrahydrofuran, benzene, toluene, dioxane and / or halogenated aliphatic hydrocarbons; the reaction is carried out at a temperature of -20°C to 70°C for 30 minutes to 24 hours.

50. The method of claim 43, wherein: When W is -OC(O)R c When Z is -OH, the compound of formula (II) reacts with the compound of formula (III) in the presence of a catalyst in an inert solvent to produce the compound of formula I.

51. The method of claim 50, wherein: The catalyst is selected from N,N-dimethylaminopyridine, an alkali metal compound catalyst, a Lewis acid catalyst, an alkaline earth metal alkoxide catalyst and / or an organic titanium catalyst; the alkali metal compound catalyst is selected from NaOH, KOH, Li2CO3, Na2CO3, NaHCO3, K2CO3, Na2WO4 or a combination thereof; the Lewis acid catalyst is selected from AlCl3, ZnCl2, SnCl4, TiCl4, FeCl3, MgCl2, Pb(OAc)2, Z n(OAc)2, Al2O(OAc)4 or a combination thereof; the alkaline earth metal alkoxide catalyst is selected from sodium methoxide, sodium ethoxide, magnesium methoxide or a combination thereof; the organic titanium catalyst is selected from butyl titanate Ti(OC4H9)4, dichlorotitanocene (Cp2TiCl2) or a combination thereof; the inert solvent is selected from N,N-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, dichloromethane, acetonitrile and / or polyhalogenated aliphatic hydrocarbons; the reaction is carried out at a temperature of -20°C to 70°C for 30 minutes to 24 hours.

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